2-halomethyl-delta2-androstenes and derivatives thereof



United tates I atent Bfibfifi Patented Mar. 5, 1963 3,080,3% 2-HALOMETHYL-M-ANDROSTENES AND DERIVATIVES THEREGF Albert Bowers, John Edwards, and .iarnes C. Orr, allot Mexico City, Mexico, assignors to Syntax 8A., Mexico City, Mexico, a corporation of Mexico No Drawing. Filed Apr. 13, 1962, Ser. No. 187,222

' 18 Claims. (Cl. zeta-397.4

The present invention relates to certain new cyclopentanophenantrene derivatives and to the method for making the same.

More particularly it relates to the novel 2-halomethyl- A -androstenes, which may be further substituted at C-l7zx by an alkyl, alkenyl or alkynyl group as well as to the 19-nor derivatives and the esters thereof.

The present invention relates also to a new method for making Za-halomethyl-androstan and l9-nor-androstanl7fl-ol-3-one derivatives, which have been described in our copending application Serial No. 107,039, filed on May 2, 1961.

The novel compounds object of our invention are potent anabolic agents with a favorable anabolic-androgenic ratio, lower the blood cholesterol level, relieve premenstrual tension and exhibit anti-estrogenic and antigonadotrophio activities. The 17a-alkenyl and alkynyl compounds are also progestational agents.

The novel compounds of the invention are represented by the following formula:

taining up to carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trirnethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and fi-chloropropionate.

In our copending patent application Serial No. 146,455, filed on- October 20, 1961, there is described the method for producing 2-hydroxymethyl-A -androsten-1713-01, the

17OC-Sllb5tltllt8d derivatives and the corresponding l9-nor compounds by reducing 2-formyl-A -androstenes and 2- formyl-AF-19-nor-androstenes with sodium borohydride.

The novel 2-halomethyl-d -compounds of the present invention are obtained from the Z-hydroXymethyl-A -androsten compounds by a method illustrated by the following equation:

OR ?R In the above formula R, R and R have the same meaning as heretofore set forth; X represents chlorine or bromine.

In practicing the process set forth above Z-hydroxymethyl-M-androsten-175-01, 2 hydroxymethyl-19-nor-A androsten-17fl-ol, the esters thereof or the corresponding 170t-SllbSlltl1ted derivatives (I) is treated with thionyl chloride in benzene solution. The reaction is effected at room temperature, for a period of time in the order of 5 minutes to 1 hour, thus producing the 3B-chloro-2- methylene derivatives (II: X =chlorine) which upon heating with lithium chloride in dimethylformamide, for a period of time of 18 to 24 hours at C. give rise to the corresponding 2-chloromethyl-A -androstenes and 19-nor-androstenes (III: X =chlorine). In a similar manner, but using thionyl bromide and lithium bromide instead of the corresponding chlorides, there are produced SB-bromo-Z-methylene and 2-,brornomethyl-A -androstenes and 19-nor-androstenes (II and III: X =bromine).

In order to obtain the 2fluoromethyl-n -androstenes object of the present invention, a Z-hydroxymethyl derivative of A -androsten-17 8-01-l9 -nor-A -androsten-17B- ol, the corresponding 17ot-alkyl, alkenyl or alkynyl derivatives or esters thereof is reacted with anhydrous hydrogen fluoride in mixture with methylene chloridetetrahydrofuran, at low temperature, preferably between -70 and 0 C. for a period of time in the order of 15 to 24 hours preferably for 18 hours, thus producing the 2-fluorornethyl-A -androsten compounds (IV).

Alternatively, the esters of the 2-halomethyl-A -androstenes object of the present invention may be obtained by conventional esterification of the free compounds (III and IV: R .=H), that is, by treatment with acid anhydrides or chlorides of less than 12 carbon atoms in pyridine solutionfor the 17-unsubstituted 2-halomethylandrostenes and l9-nor-androstenes or With acid anhydrldes in benzene solution and in the presence of ptoluenesulfonic acid for the C-Zi1kyl, alkenyl' and alkynyl derivatives.

The new method for producing 2a-halomethyl 17a- FHiC-I by the method illustrated by the following equation:

substituted androstan derivatives is illustrated by the following sequence of reactions:

R i n XHzC Xroo E on: on i R3 I --R3 R n l Xmo- Kano-- VIII) no v11 In the above formulas R, R and X have the same meaning as previously set forth; R represents a lower alkyl or alkynyl group.

In practicing the process set forth above, a Z-halomethyl derivative of A -androsten-17B-ol, which is further substituted at C-17ct by an alkyl or alkynyl group, or the corresponding 19-nor-derivatives (V), is treated with 1.1 molor equivalents of a peracid, preferably monoperphthalic or perbenzoic acid, to give the corresponding 2,8- halomethyl-2a,3a-oxido compounds (Vi). Upon treatment of these epoxides with lithium aluminum hydride in tetrahydrofuran solution at reflux temperature and for a prolonged period of time, preferably during 18 hours, the epoxide ring is opened, thus producing the Zea-halomethyl-3a-hydroxy derivatives (VII), with concomitant saponification at C-17, when an ester has been used as the starting material.

Oxidation of the above compounds with 8 N chromic acid in acetone solution or with chromic acid in acetic acid produce the corresponding 3-ketone (Villz R =hydrogen), which are then esterified by the methods hereinabove set forth, thus producing the esters of Z a-halomethyl 17ot-alkyl and l7a-alkynyl-androstan-175-01-3- one and the esters of 2a-halomethyl-17a-alkyl and 17aalkynyl-19-nor-androstan-l7r3-ol-3-one (VII: R =acyl).

By partial hydrogenation of the 2-halornethyl-17aallrynyl compounds (VH1: R =alkynyl) using 2% palladium on calcium carbonate as catalyst and in pyridine derivatives.

Thus for example, starting from Z-chloromethyl-lhethynyl-d -androsten-l75-01 acetate there are obtained successively 2,8-chloromethyl-2a,3ot-oXido-l7a-ethynyl-androstan-17B-ol acetate, 2ot-chloromethyl-17ot-ethynyl-an- 2a-chlorornethyl-l7a-ethynyl-androstan-17,6-ol-3-oue and Za-chlommethyl-l7a-vinyl-androstan-l7fi-ol-3-one.

In another aspect of the present invention the 20:- chloromethyl, Za-bromomethyl and 2a-fluoromethyl-androstan-l7fi-ol-3-one, the 17a-alkyl substituted derivatives and the corresponding 19-nor compounds are obtained solution there are obtained the 2ot-halornethyl-17a-alkenyl In the above formulas R, R and X have the same meaning as heretofore set forth; R represents hydrogen or lower alkyl.

In practicing the process outlined above, a 2-halomethyl derivative of A -androsten-17B-ol, which may be further substituted at C-17u by a lower alkyl group, or the corresponding 19-nor derivatives (IX), is treated with a current of diborane in a solvent such as tetrahydroiuran. Upon subsequent reaction with aqueous alkali and hydrogen peroxide there is formed the 3u-hydroxy-2/3-halomethyl derivative (X) which is converted into the 3-keto compound (XI) upon reaction with chormium trioxide in acetic acid or acetone solution.

The inversion of the steric configuration of the halomethyl substituent at C-2 is effected by acid treatment, preferably using anhydrous hydrogen chloride in chloroform solution, thus producing 2ot-halomethyl androstan- 17fl-ol-3-one, 2ot-halomethyl-l7a-alkyl androstan-l75-ol- 3-one and the corresponding l9-nor compounds and esters (XII).

The novel compounds represented by Formulas VIII and XII are potent anabolic agents having a favorable anabolic-androgenic ratio; exhibit anti-estrogenic and anti-gonadotrophic activities; relieve premenstrual tension, lower the blood cholesterol and have anti-fibrillatory properties.

The following examples serve to illustrate but are not intended to limit the scope of the present invention.

PREPARATION 1 To a solution of 5 g. of Z-hydroxymethyl-Not-methyl- A -androsten-l7fi-ol in cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonic acid and 15 cc. of acetic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and Water, and the resulting mixture stirred to effect hydrolysis of the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from ether-hexane produced Z-acetoxymethyl-17a-rnethyl-A -androsten-17,6-ol-acetate.

A mixture of 2 g. of the above compound and 20 cc. of a 1% potassium hydroxide solution was stirred for 1 hour at 0 C.; it was then poured into water and the formed precipitate collected by filtration, thus giving 2- hydroxymethyl 17a methyl A androsten 17,8 olacetate.

PREPARATION 2 By the same method of Preparation 1, Z-hydroxymethyl-17a-methy1-19-nor-A androsten-17,8-01, 2-hydroxymethyl-l7a-ethyl-A -androsten--01, 2-hydroxymethyl- 17ct-vinyl-A 19-norandrosten-l7B-ol, 2 hydroxymethyll7a-ethinyl-A -androsten-17,8 01 and 2 hydroxymethyl l7a-ethinyl-A -19-nor-androsten-17/3-ol were converted into the corresponding 17-acetates, namely 2-hydroxymethyl-l7a-rnethyl-19-nor-A -androsten-17,3-01-acetate, 2- hydroxy-methyl-l7a-ethyl-A -androsten-17 3-ol-acetate, 2- hydroxy-methyl-17a-vinyl-A -19-nor-androsten-17/3-ol acetate, 2-hydroxymethyl-17u-ethinyl-A -androsten 1713 olacetate and 2-hydroxymethyl-l7ot-ethinylal9-nor-A -androsten-17fi-ol acetate.

Example I A solution of 2.5 g. of 2-hydroxymethyl-A -androsten- 175-01 in 250 cc. of dry benzene thiofene free was treated with 2.5 cc. of freshly distilled thionyl chloride and the reaction mixture was kept at room temperature during 1 hour. It was then diluted with water and the organic layer washed well with 5% sodium carbonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuo. The residue was filtered through a column of 100 g. of acetic acid washed alumina using 500 cc. of benzene-hexane 1:1 as solvent. The crystalline fractions were combined and recrystallized from methanol, thus affording 1 g. of 3fl-chloro-2-methylene-androstan-17B-ol.

A mixture of the above compound (1 g.), 1 g. of lithium chloride and 100 cc. of dimethyl formamide Was heated on the steam bath for 18 hours. Water was added and the formed precipitate collected by filtration, thus giving the crude 2-chloromethyl-A -androsten-175-01 which was purified by recrystallization from methanolwater.

A mixture of 1 g. of the latter compound, 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight. It was then poured into water, and the formed precipitate collected by filtration, thus producing the acetate of 2-chloromethyl-A -androsten- 1713-01.

A solution of 2 g. of 2-hydroxy-methyl-A -androsten- 1713-01 in 80 cc. of methylene chloride was cooled to --70 C. and added to a mixture of 8 g. of anhydrous hydrogen fluoride and 144 g. of tetrahydrofuran previously cooled to 70 C. in a Dry Ice-acetone bath. The mixture was kept standing at -10 C. for 18 hours. It was then carefully poured into water and the excess of hydrogen fluoride decomposed by adding 50 g. of sodium carbonate. The product was then extracted with methylene chloride and the organic extract washed to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was dissolved in 100 cc. of hexane-benzene (1:1) and filtered rapidly through a column of 50 g. of acetic acid washed alumina. The crystalline fractions were combined and recrystallized from methanol, thus giving 0.7 g. of 2-fluoromethyl-A -androsten-17B-ol.

A solution of 1 g. of the latter compound in 4 cc. of pyridine was treated with 2 cc. of benzoyl chloride and then heated on the steam bath for 1 hour. The mixture was then poured into ice water and the formed precipitate collected, washed with water and dried. Recrystallization from methylene chloride-hexane afiorded the benzoate of 2-fluoromethyl-A -androsten-1713-01.

Example III A solution of 5 g. of 2-hydroxymethyl-M-androsten- 17,8-01- in 500 cc. of dry benzene, thiophene free was treated with 5 cc. of freshly distilled thionyl bromide and the mixture kept at room temperature for 1 hour. It was then washed with water, 5% sodium carbonate solu- 'tion and water to neutral, dried and evaporated to dryness under vacuo. The residue was dissolved in 1 1t. of

benzene-hexane 1:1 and filtered through a column of 200 g. of acetic acid washed alumina thus producing 318- bromo-2-rnethylene-androstan-175-01.

Example IV By following the method of Example I the compounds listed below under I were treated with thionyl ch oride in benzene solution to give the corresponding 3B-chloro- Z-methylene compounds (II), which in turn were convented into the 2-chloromethyl-A -androsten derivatives (I11).

I II III By following the method of Example II, 5 g. of 2- hydroxymethyl-17a-methyl-A -androsten-17,8-ol were converted into 2-fluoromethyl 17a methyl-A -androsten- 175-01.

To a solution of 1 g. of the latter compound in 20 cc. of anhydrous benzene there were added 200 mg. of ptoiuenesulfonic acid and 2 cc. of acetic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to efi'ect hydrolysis of the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from ether-hexane produced the acetate of 2-fluoromethyl-17umethyl-A androsten-175-01.

Example VI In accordance with the esterification method of th preceding example 2 chloromethyl 17a methyl-A .androsten-lm-ol was converted into the corresponding acetate.

In a similar manner, but using caproic and propionic anhydride as esterifying agents, there were produced caproate and the propionate of Z-chloromethyl-lhmethy l-d -androsten-175-01.

Example VIZ of Z-bromomethyl-17a-vinyl-A -androsten-1713-01.

Example VIII A slow stream of dibonane was passed through a solution of 10 g. of Z-chlorornethyl 17a-metl1yl-A =androsten-17 8-ol acetate in 150 cc, of tetrahydrofuran for 1 hour. (After 20- minutes the solution became warm and then the temperature slowly sub-sided.) The excess of diborane was decomposed by careful addition of Water. Then 1 it. of water was added and the. formed precipitate was filtered, washed and dried, thus giving 9.6 g. of the organoboroncompound.

This material was dissolved in 200 cc. of tetrahydrofuran and treated with 9 g. of sodium hydroxide previously dissolved in 25 cc. of water, and 45 cc. of 35% hydrogen peroxide, stirring and keeping the temperature around 15 C. The mixture was stirred for 2 hours, after this time, the precipitated product was filtered,

washed and dried, thus producing 25-chloromethyl-17amethyl androstane-3u,17B-diol-17-acetate.

A solution of 2 g. of the above compound in 50 cc. of acetone was cooled to C. and treated under an atmosphere of nitrogen and with stirring, with a solution of 8 N chrornic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc, of concentrated sulfuric acid and diluting with water to 100 cc.), until the color of the reagent persisted in the mixture. It was stirred for minutes further at 0-5 C. and diluted with water. The precipitate was collected, washed with water and dried under vacuum, thus affording a crude product which upon recrystallization from acetone-hexane gave ZB-chloromethyl 17cc methyl-androstan-l7fi-ol-3-one acetate.

A solution of 1 g. of the preceding compound in 50 cc. of dry chloroform was treated with 1 cc. of dry chloroform saturated with hydrogen chloride. After 3 hours at room temperature the reaction mixture was washed with 5% sodium bicarbonate solution and water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product after crystallization from ether-pentane afiorded 0.4 g. of 2achloromethyl-l7a-methyl-androstan-l7fl-ol-3-one acetate.

Example 1X By following the method of Example II, 5 g. of 2-hydroxymethyl-lh-ethinyl-19-nor-A -androsten-17 3-01 was converted into Z-fluoromethyl-17e-ethinyl-19-nor-A -andr0sten-175-ol. Esterification of the above compound with acetic anhydride in benzene solution and in the presence of p-toluenesulfonic acid gave the corresponding acetate.

A solution of 2.5 g. of 2-fluoromethyl-l7u-ethinyl-19- nor-A -androsten-17,8-ol-acetate in 100 cc. of chloroform was cooled to 0 C. and mixed with 1.4 g. (1.1 molar equivalents) of monoperphthalic acid in ether solution. The mixture was kept at room temperature for 20 hours, diluted with Water, the organic layer was separated, washed with aqueous sodium bicarbonate solution and then with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane gave 2,8-fiuoromethyl-2a,3a-oxido-17aethinyl-lQ-nor-androstan-17(3-01 acetate.

A solution of 1 g. of the preceding epoxide in 50 cc. of tetrahydrofuran was added over a 30 minute period to a stirred suspension of 1 g. of lithium aluminum hydride in 50 cc. of anhydrous tetrahydrofuran. The mixture was refluxed for 18 hours, then cooled and cautiously treated with 5 cc. of ethyl acetate and 2 cc. of water. Solid sodium sulfate was added, the inorganic material filtered off and thoroughly washed with hot ethyl acetate, the combined organic solutions upon evaporation yielded a crude material, which was purified by crystallization from acetone-hexane thus giving 2a-fluoromethyl-l7uethinyl-19-nor-androstan-3a,l7,8-diol.

Upon oxidation of the above diol with 8 N chromic acid in acetone solution, in accordance with the method of Example VIIl there was obtained 2a-fiuoromethyl-17ot ethinyl-l9-nor-androstan-17,8-ol-3-one which was esterified with propionic anhydride in benzene solution and in the presence of p-toluenesulfonic acid, to give the corresponding propionate.

Example X By following the methods of Examples II and VIII, the acetate of 2-hydroxymethyl-l9-nor-A2-androsten-17fl- 01 was converted successively into 2-fluoromethyl-A -l9- nor-androsten-17fl-ol-acetate, 2,8-fluoromethyl-l9-nor-androstane-Sor,l7fl-diol-l7-acetate and 2a-fluoromethyl-l9- nor-androstan-17,8-ol-3-0ne-acetate.

Example XI A solution of 1 g. of 2u-fluoromethyl-17a-ethinyl-19- nor-androstan-17,6-ol-3-one,in 40 cc. of pyridine was hydrogenated at 25 C. and 570 mm. in the presence of d 400 mg. of pre-hydrogenated 2% palladium calcium carbonate catalyst.

When 1.1 molar equivalent of hydrogen had been absorbed, the reaction was stopped, the catalyst separated by filtration through celite, washed with ethyl acetate and the combined solutions evaporated to dryness in vacuo, yielding the crude vinyl derivative. This crude product was dissolved in ethyl acetate, the organic solution washed with dilute hydrochloric acid and Water to neutral, dried and evaporated to dryness. Recrystallization from acetone gave Za-fluoromethyl-lh-vinyl-19-nor-androstan- 17/3-ol-3-one.

The above compound was esterified with acetic, propionic and undecenoic anhydride in benzene solution and in the presence of p-toluenesulfonic acid, thus producing the corresponding esters.

Example XII Examples I and IX were repeated but using 2-hydroxymethyl-17e-ethyl-A -androsten-17fi-ol acetate as starting material. There were thus obtained successively 2-meth ylene 3,8 chloro 17a ethyl androstan 17,8 olacetate, 2 chloromethyl 17a ethyl A androsten- 17 3-01 acetate, 2,8-chloromethyl-2e,3a-oxido-17a-ethylandrostan-17/8-ol acetate, 2ot-chloromethyl-l7u-ethyl-androstane-3a,17p-diol, Za-chloromethyl-l7a-cthyl-androstan-17fi-ol-3-one and 2a-chloromethyl-l7a-ethyl-androstan-l7fl-ol-3-one propionate.

Example XIII 5 g. of 2-chloromethyl-A -androsten-175-01 were converted into the corresponding benzoate by treatment with benzoyl chloride in pyridine solution.

The above benzoate was then subjected to the reactions described in Example VIII, thus producing Zfi-chloromethyl-androstane-f'm,175-diol 17 benzoate, Zfi-chloromethyl-androstan-17fi-ol-3-one benzoate and Z-oc-ChlOIO- methyl-androstan-l7fi-ol-3-one benzoate.

In a similar manner, starting with 2-bromomethyl-A androsten-Nfi-ol there were obtained successively 2-bromomethyl A androsten 17 3 ol-benzoate, Zfl-bromo- 'methyl-androstane-3ot,17,8-diol 17-benzoate, 2,8-bromomethyl-androstan-17 8-ol-3-one benzoate and 2a-bromomethyl-androstan-17,6-01-3-one benzoate.

Example XIV In accordance with the method of Example III, 2 g. of 2 hydroxymethyl l7ot-ethinyl-androstan-17fl-ol acetate were treated with thionyl-bromide, to give 3,8-bromo-2- methylene-17a-ethinyl-androstan-17 3-01 acetate, which upon reaction with lithium bromide in dimethyl-formamide gave Z-bromethyl-l7a-ethinyl-A -androsten-1713-01- acetate.

The latter compound was then converted into 2oz-b1'0m0- methyl-l7a-ethinyl-androstan-175-01-3-0116, by following the method of Example IX.

Example XV 2 g. of 2-chloromethyl-17a-ethinyl-A -androsten-17 3-01- acetate were oxidized with monoperphthalic acid, in accordance with the method of Example IX, and the resulting epoxide refluxed for 18 hours with lithium aluminum hydride thus giving 2a-chloromethyl-17a-ethiny1-androstane-Zia,17fi-diol.

A solution of 250 mg. of chromic acid in 5 cc. of acetic acid was added dropwise to a stirred solution of 1 g. of 2u-chloromethyl-l7ct-ethinyl-androstan-3a,l7fl-diol in 75 cc. of glacial acetic acid, while the temperature was maintained around 20 C. After 2 hours at room temperature, the mixture was poured into ice water and the formed precipitate collected, washed with water and recrystallized trom methanol, thus giving 2a-chloromethyl- 17d-ethinyl-androstan-17B-ol-3-one.

The above compound was esterified with acetic and cyclopentylpropionic anhydride in benzene solution and in the presence of p-toluenesulfonic acid, to give the acetate and the cyclopentylpropionate of 2m-chloromethyl- 17a-ethinyl-androstan-17B-ol-3-one.

Example XVI By following the method of Example XI, Zwbromomethyl-17a-ethinyl-androstan-17B-ol-3-one and Zea-chloromethyl 17a-ethinyl-androstan-17/3-ol-3-one cyclopentylpropionate were converted respectively into 2a-bromomethyl-l7a-vinyl-androstan-17/8-ol-3-one and 2a-chloromethyl-17a-viny1-androstan-17fl-ol-3-one cyclopentylpropionate.

Example X VZI In accordance with the methods of Examples II and VIII, 5 g. of 2-hydroxymethy1-17a-methyl-19-nor-A -androsten-17fl-ol acetate were converted successively into 2-fluoromethyl-17a-methyl 19 nor-A -androsten-flfi-ol acetate ZB-fluoro-methyl-17a-methyl-l9-nor-androstan-3a, 17fi-diol-17-acetate, Zfi-fluoromethyl-17u-methyl-19 nor androstan 17fi-ol-3-one acetate and Za-flHOIOmGthYI-I'Yamethyl-19-nor-androstan-17/3-ol-3-one-acetate.

We claim:

1. A compound of the following formula:

XHQ l 7. Z-fluoromethyl-17a-ethynyl-A -androsten-175-01.

8. The acetate of Z-fluoromethyl-17a-methy1-A -androsten-17fl-ol.

9. 2oz fluoromethyl 17oz ethynyl 19 nor androstan-17fi-ol-3-one.

10. 2a fiuoromethyl 17a vinyl 19 nor androstan-l7fi-ol-3-one.

11. 2a chloromethyl 17a ethynyl androstan 175- ol-3-onc.

12. 2a chloromethyl 17oz vinyl androstan 17B- 01-3-one-cyclopenty1propionate.

13. 2a bromornethyl 17a ethynyl androstan 1718- ol-3-one.

14. The method for the production of Za-halomethyl- 17-substituted androstanes which comprises treating the corresponding 2-ha1omethyl-A -compound with a peracid, reacting the 2a,3a-epoxide thus formed with lithium aluminum hydride in a suitable solvent to give the 2a-halomethyl-3a-hydroxy compound, and oxidizing with chromium trioxide to form the corresponding 3-keto compound.

15. The method for the production of a compound selected from the group consisting of 2oc-halomethyl-androstan-l7p-ol-3-one compounds and the corresponding 17a-alkyl derivatives, which comprises treating 'a corresponding 2-hal0methy1-A -androstan-17,8-01 with diborane, followed by hydrogen peroxide-alkaline treatment, to give the corresponding 2fi-halomethyl-3a-hydroxy compound, oxidizing to the 3-keto and thereafter treating with acid to form the corresponding 2a-halomethyl-androstan-175- 0l-3-one derivative.

16. The method of claim 15 wherein the 2a-halomethyl derivative is the chloromethyl derivative, the peracid is the monoperphthalic acid, the suitable solvent for the reduction is tetrahydrofuran.

17 The method of claim 15 wherein the 2a-halomethyl derivative is the bromomethyl derivative, the peracid is the monoperphthalic acid, the suitable solvent for the reduction is tetrahydrofuran.

18. The method of claim 15 wherein the 2a-halomethyl derivative is the fluoromethyl derivative, the peracid is the monoperphthalic acid, the suitable solvent for the reduction is tetrahydrofuran.

No references cited. 

14. THE METHOD FOR THE PRODUCTION OF 2A-HALOMETHYL17-SUBSTITUTED ANDROSTANES WHICH COMPRISES TREATING THE CORRESPONDING 2-HALOMETHYL-$2-COMPOUND WITH A PERACID, REACTING THE 2A,3A-EXPOXIDE THUS FORMED WITH LITHIUM ALUMINUM HYDRIDE IN A SUITABLE SOLVENT TO GIVE THE 2A-HALOMETHYL-3A-HYDROXY COMPOUND, AND OXIDIZING WITH CHROMIUM TRIOXIDE TO FORM THE CORRESPONDING 3-KETO COMPOUND. 